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WO1998011086A1 - Derives de chromone et inhibiteurs de la mort des cellules nerveuses contenant lesdits derives - Google Patents

Derives de chromone et inhibiteurs de la mort des cellules nerveuses contenant lesdits derives Download PDF

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Publication number
WO1998011086A1
WO1998011086A1 PCT/JP1997/002402 JP9702402W WO9811086A1 WO 1998011086 A1 WO1998011086 A1 WO 1998011086A1 JP 9702402 W JP9702402 W JP 9702402W WO 9811086 A1 WO9811086 A1 WO 9811086A1
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group
isopropoxy
thio
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dichloromethane
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Japanese (ja)
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Yasushi Igarashi
Masahide Tanaka
Erika Yanagisawa
Takuji Yamaguchi
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Tsumura and Co
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Tsumura and Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
    • C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
    • C07D311/54—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 substituted in the carbocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a chromone derivative which can be used as a therapeutic agent for a disease caused by nerve cell death, and a nerve cell death inhibitor containing the derivative.
  • Neuronal death and neurotrophic factor Neurotrophic Facor: NTF
  • Neurotrophic Facor Neurotrophic Facor: NTF
  • NGF nerve growth factor
  • BSC-1CB-2 the oncogenic gene product BSC-1CB-2 has been used as a biological substance to save nerve cells from cell death by suppressing the expression of such suicide mechanisms in nerve cells.
  • a neurotrophic factor such as nerve growth factor cannot be received (or the neurotrophic factor is inadequate)
  • a drug with an effect of rescuing induced neuronal death an effect of inhibiting neuronal death
  • a compound which can be used for treatment of many diseases and has a nerve cell death inhibitory effect there has been a demand for the development of a compound which can be used for treatment of many diseases and has a nerve cell death inhibitory effect.
  • R 2 are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkenyl group or an acyl group, and R 3 represents an oxygen atom, a zeo atom, one SO-, S- 2 — or one NH
  • R 7 represents a substituted or unsubstituted phenyl group, an aralkyl group or a heterocyclic group, and represents a hydrogen atom or a lower alkoxy group.
  • chromone derivative represented by are only compounds having an R hydrogen atom or a glycoxy group (W092 09594).
  • the chromone-based conductor represented by the formula (II) has a nerve cell death inhibitory effect. Disclosure of the invention
  • An object of the present invention is to provide a novel compound having a neuronal cell death inhibitory effect and a neuronal cell death inhibitor containing the compound.
  • the present invention provides the following formula (I):
  • R Karubokishi - 6 - alkyl group, Karubokishi C Aruke alkenyl group, C, - e - alkoxy one - alkyl, C, -6 - one local Boniru group, - alkylthio -C physician 6 - alkyl group, d-6 - alkylsulfamoyl Finiru d - alkyl, C> - 6 - alkyl sulfonyl Lou C 1-6 - alkyl le group, d-6 - alkylsulfonyl group , C 6 -alkyl-carbonyloxy C, -6 -alkyl group, 6 -alkoxy-carbonyl-C, -6 -alkyl group,
  • “(:,-6-alkyl)” in the group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 11-ethylpropyl group and hexyl group.
  • Bok 6 - alkoxy includes, for example main Bok carboxymethyl Group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, 1-ethylpropyloxy group, and hexyloxy group.
  • alkylthio one alkylthio one C L - 6 - in the alkyl group as "- - 6 ( ⁇ alkylthio O", for example a methylthio group, Echiruchio group, propylthio group, isopropenyl Piruchio group, butylthio group, isobutylthio group, sec- Examples include a butylthio group, a tert-butylthio group, a pentylthio group, an isopentylthio group, a 1-ethylpropylthio group, and a hexylthio group.
  • Examples of the branched alkyl group having 3 to 6 carbon atoms include an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, and a 1-ethylpropyl group.
  • Examples of the aliphatic acetyl group having 2 to 6 carbon atoms include an acetyl group, a propionyl group, an isoptyryl group, a bivaloyl group, an acryloyl group, and a methacryloyl group.
  • substituted carbamoyl groups include dexameyl groups that are mono- or di-substituted with de-alkyl, phenyl, pyridyl, and piperidyl groups.
  • the Ct-s-alkyl group, phenyl group, Pyridyl group and piperidyl group are a halogen atom such as a chlorine atom, - alkoxy one carbonyl groups, C physician 6 - alkylthio group, - an alkoxy group, d-6 - alkyl group, a carboxy group, a hydroxyl group, may be substituted with at least one substituent selected from Shiano group and a formyl group .
  • Examples of the substituted thiocarbamoyl group include thiocarbamoyl mono- or di-substituted with d-6-alkyl, phenyl, pyridyl, or piperidyl.
  • the d-6-alkyl group, phenyl group, pyridyl group and piperidyl group are a halogen atom such as a chlorine atom, d-6-alkoxymonocarbonyl group, C »-6 monoalkylthio group, C, - 6 - alkoxy groups, C primary alkyl group, carboxy group, hydroxy group, may be substituted with at least one substituent selected from Shiano group and formyl group.
  • Substituted i Ichipipe lysine alkenyl group for example, a hydroxyl group, hydroxy Sea d-6 - alkyl group, (: I 6 - alkoxy - C, - 6 - mono- or di-substituted alkyl group, with carboxy sheet group
  • substituted 1-pyrrolidinylcarbonyl group include a hydroxyl group, a hydroxy-6-alkyl group, a dS-alkoxy-1-d-6-alkyl group, and a carboxyl group.
  • Shi group examples include 1 one pyrrolidinylcarbonyl group which is monosubstituted or disubstituted substituted 1 one piperazinylcarbonyl group, for example, a hydroxyl group, hydroxy Sea - alkyl groups, C Bok 6 - alkoxy - C - 6 - alkyl group, carboxy sheet 1 one piperazinylcarbonyl group which is mono- or disubstituted and the like in the group substituted morpholinocarbonyl groups.
  • the substituted or unsubstituted benzenesulfonyl group for example C, - 6 - alkyl group, a hydroxyl group, hydroxy - C, - 6 - alkyl, C t - 6 - alkoxy eleven alkyl group, mono-substituted with a force Rubokishi group Or a di-substituted benzenesulfonyl group.
  • the medicinal substance of the chromone derivative of the present invention is a compound in which R is a hydrogen atom in the above formula (I), that is, 2-[(4-hydroxyphenyl) thio] -17-isopropoxy-1,5,6-dimethyl. It is methoxy-4H-chromen-1-one, and the chromone derivative of the present invention also improves the bioavailability of the medicinal substance.
  • R in the formula (I) is particularly preferably the following, from the viewpoint of the neuronal cell death inhibitory effect and bioavailability.
  • the compound of the present invention can be used as a pharmaceutically acceptable salt depending on the type of the functional group, and examples of such a salt include hydrochloride, phosphate, sulfate, and fumarate. And acid addition salts such as maleic acid salts, and alkali metal salts such as sodium salts.
  • the compound (I) of the present invention is preferably a compound wherein R in the above formula (I) is a hydrogen atom, that is, 2-[(4-hydroxyphenyl) thio] -17-isopropoxy-1,5,6- Of dimethyloxy 4 H-chromen-4-one (5,6-dimethyloxy 2- (4-hydroxyphenylthio) -7-isopropoxycyclomone described in Example 22 of WO 92/09594)
  • the phenolic hydroxyl group can be produced by etherification, esterification, carbonate esterification, carbamic acid esterification, thiocarbamic acid 0-esterification, sulfonic acid esterification or phosphoric acid esterification according to a conventional method. .
  • a substituent corresponding to R contains a functional group involved in the reaction, for example, a hydroxyl group or a rubboxyl group in the esterification of rubamic acid
  • the functional group is protected with an appropriate protecting group, and After performing a reaction such as esterification, the protecting group is eliminated.
  • the protecting group for a hydroxyl group include a tert-butyldimethylsilyl group
  • examples of the protecting group for a carboxyl group include a tert-butyl group.
  • the product may be purified by a commonly used technique, for example, column chromatography using silica gel or the like as a carrier, or a recrystallization method using methanol, ethanol, chloroform, dimethyl sulfoxide, water, or the like.
  • a commonly used technique for example, column chromatography using silica gel or the like as a carrier, or a recrystallization method using methanol, ethanol, chloroform, dimethyl sulfoxide, water, or the like.
  • the elution solvent for column chromatography include chromatographic form, acetone, hexane, dichloromethane, ethyl acetate, and a mixed solvent thereof.
  • the chromone derivative (I) of the present invention and a pharmaceutically acceptable salt thereof have a nerve cell death inhibitory effect, and are induced when a neurotrophic factor cannot be received (or the neurotrophic factor is deficient).
  • Diseases caused by cell death for example, Ma's disease [Pr. NAS], Vol. 83, 923 1-9235, 1986], Down's syndrome [Pr. NAS], 88, 1793-1797, 1991], vascular dementia [Journal of Neurology (J. Neur osci.), 11 Vol. 9, 2914-29 19, 1991], Parkinson's disease [Netiyah (Nature), 350, 230-232, 1991], amyotrophic lateral sclerosis (An n. N euro 1.) 10, 499-505, 1981] is there.
  • the compound obtained in the example showed no death by oral administration of lg / kg.
  • the compound of the present invention has extremely low toxicity and high safety.
  • the dose and formulation of the compound of the present invention will be described.
  • the compounds of the present invention can be administered to animals and humans as they are or together with conventional pharmaceutical carriers.
  • the dosage form is not particularly limited and may be appropriately selected and used as needed. Examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, and parenteral preparations such as injections and suppositories. Can be
  • Oral preparations are produced by a conventional method using, for example, starch, lactose, sucrose, mannite, carboxymethyl cellulose, corn starch, inorganic salts and the like.
  • a binder In this type of preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a fragrance, and the like can be appropriately used in addition to the above-mentioned excipients. Specific examples are as follows.
  • Starch hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, low-substituted hydroxypropylcellulose.
  • Talc waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.
  • the compounds of the present invention can also be administered as suspensions, emulsions, syrups, and elixirs. These various forms may contain flavoring agents and coloring agents.
  • Intravenous, intravenous, subcutaneous, and intramuscular injections are appropriate.
  • This parenteral preparation is manufactured according to a conventional method, and as a diluent, generally, distilled water for injection, saline, aqueous glucose solution, vegetable oil for injection, sesame oil, laccase oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. Can be used. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. In addition, from the viewpoint of stability, the parenteral preparation can be frozen after filling into a vial or the like, water can be removed by ordinary freeze-drying branching, and a liquid preparation can be prepared from the freeze-dried product immediately before use. Further, if necessary, a tonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added as appropriate.
  • parenteral preparations include liquids for external use, irritants, etc. Suppositories and the like can be mentioned, and are manufactured according to a conventional method. BEST MODE FOR CARRYING OUT THE INVENTION
  • Example 7 7-Isopropoxy-1,5-dimethoxy-2-[[4- (methoxymethoxyphenyl) phenyl] thio] —4H-chromene-4-one 2-[(4-Hydroxyphenyl) thio 7-isopropoxy-1,6-dimethoxy 4H-chromene 41
  • One-one 500 mg (1.29 mmole) of N, N-diisopropyl 0.4 mi (2.3 mmole) of tilamine and 0.15 ml (1.96 mmole) of chloromethyl methyl ether were added, and the mixture was stirred at room temperature for 16 hours.
  • Example 1 1 2 — [[4-[(Isobutoxycarbonyl) oxy] phenyl] thio] —7-isopropoxy-5,6-dimethoxy 4 H—chromene 4-one
  • Example 1 2-[[4-[(ethoxycarbonyl) hydroxy] phenyl] thio] — 7-isopropoxy-5,6-dimethoxyloxy 4 H-chromene 4-one
  • Example 1 4 4-[(7-Isopropoxy-1,5,6-dimethoxy-1-4-oxo-4H-chromen-12-yl) thio] phenyl acetate
  • ⁇ -NR (CDC1 3) 8.01 (dd, 3.9H2,1.5Hz, lH), 7.71 (dd, 4.9Hz, 1.5 ⁇ , 1 ⁇ ), 7.65 (d, 8.8Hz, 2H), 7.34 (d, 8.8Hz, 2H), 7.21 (dd, 4.9Hz, 3.9Hz, LH), 6.59 (s, lH), 5.89 (s, 1s), 4.63 (hept, 5.9Hz, lH), 3.92 (s, 3H), 3.85 (s , 3H), 1.43 (d, 5.9Hz, 6 ⁇ )
  • ⁇ -NR CDCU 7.58 (d, 8.7Hz, 2H), 7.22 (d, 8.7Hz, 2H), 6.60 (s, lH !, 5.82 (s, 1 ⁇ ), 4.62 (hept, 6.0Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.65 (m, 4H), 2.48 (t, 5.1 Hz, 4H), 2.36 (s, 3H), 1.43 (d, 6.QHz, 6H)
  • ⁇ -NR CDCU 7.61 (d, 8.6Hz, 2H), 7.22 (d, 8.6Hz, 2H), 6.60 (s, lH), 5.78 (s, lH), 4.62 (hept, 6.0Hz, lH), 4.38 (m, 2H), 4.00 (m, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.50 (m, 2H), 2.97 (m, 2H), 2.88 (brs, 3H), 1.43 (d, 6.0Hz, 6H)
  • Example 58 2 [[4-[[N- (3-hydroxybutyral) -1-N-methylcaprubamoyl] oxy] phenyl ⁇ thio] -17-isopropoxy-1,5,6-dimethoxy-14H— Chromen One 4—On
  • Example 6 1 2 [[4 — [[(4-Hydroxypiperidino) carbonyl] oxy] phenyl] thio] -17-isopropoxy-1,5,6-dimethyloxy-4H—chromene 41 On
  • tert-Butyl 1- (formyl form) 1-L-proline
  • 2-[(4-hydroxyphenyl) thio] -17-isopropoxy-1,5,6-dimethyloxy 500 mg (1.29 mmole) of 1-4H-chromen-4-one was added, and the mixture was stirred at room temperature for 22 hours.
  • Dichloromethane was added, and the mixture was washed with 2N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline, and dried over anhydrous magnesium sulfate.
  • Example 65 2 [[4-[[[(S) —2 -— (Hydroxymethyl) -1-1-pyrrolidinyl] carbonyl] oxy] phenyl] thio] -17-isopropoxy 5,6-dimethyloxy 4H— Chromen 4—On
  • Example 66 7-Isopropoxy-5,6-dimethoxy-2-[[4-[[[(S) —2- (methoxylmethyl) -111-pyrrolidinyl] carbonyl] oxy] phenyl] thio] One 4 H—Chrome 4 One On
  • ⁇ -NR (CDC1 3) 7.58 (d, 8.7Hz, 2H
  • Example 70 2-[[4-[[N, N-bis (2-hydroxylexetyl) dirubamoyl] oxy] phenyl] thio] -17-isopropoxy-1,5,6-dimethoxy-4H-chromene-4 One year old
  • ⁇ -NR CDCU 7.58 (d, 8.7 ⁇ , 2 ⁇ ), 7.21 (d, 8.7Hz, 2H), 6.59 (s, 1H), 5.83 (s, 1H), 4.62 (hept, 6.1Hz, lH), 3.92 (s, 3H), 3.85 (s, 3H), 3.88-3.70 (m, 4H), 3.64 (t, 5.6Hz, 2H), 3.53 (t, 5.6Hz, 2H!, 1.43 (d, 6.lHz, 6H), 0.91 (s, 18H), 0.087 (s, 6H), 0.081 (s, 6H)
  • Example 7 7-Isopropoxy-5,6-dimethoxy-2-[[4- (methylsulfonylmethoxy) phenyl] thio] -14H-chromene-14one
  • Example 8 7-Isopropoxy-5,6-dimethyloxy-2-[[4-[(methylthio) methoxy] phenyl] thio] obtained in Example 8—4H-chromene 4-one 2.00 g (4.466 ole) in 20 ml of dichloromethane was added dropwise with a solution of 776 mg (4.49 mmole) of m-chlorobenzoic acid in 15 ml of dichloromethane, and the mixture was stirred at room temperature for 3 hours.
  • Example 72 7-Isopropoxy-5,6-dimethoxy-2-[[4- (methylsulfinylmethoxy) phenyl] thio] -4H-chromen-14-one 7 obtained in Example 8 —Isopropoxy— 5,6-Dimethoxy-1 2— [[4-1 [(Methylthio) methoxy] phenyl] thio] -14H-Chromen-4-one
  • a solution of 200 mg of chlorobenzoic acid (1.16 inclusive) in dichloromethane (5 ml) was added dropwise, and the mixture was stirred at room temperature for 23 hours.
  • the nerve cell is alive because the protein that causes cell death is not synthesized.
  • NGF NGF-like growth factor
  • HBSS solution Hanks 'Balanced Salt Solution (1L powder from Hanks' Balanced Salt Solution (HBSS), Sigma) to 1L 15mM After dissolving in (HEPES, Wako) solution (PH7.2), sterilized through a 0.22 m filter (hereinafter referred to as “HBSS solution”) was used.
  • Lattice Purchase a rat (Japan SLC) on the 12th day of confirmed pregnancy of the Wistar (Wis ar) lineage, which is a special pat hogen (free stf). The first day of pregnancy was used.
  • the right and left uterine horns containing a total of about 10 fetuses on average, were taken out with a flame-sterilized pincer and a dissecting scissors, and a 100 mm diameter Petri dish containing the HBSS solution (Faicon) ).
  • the endometrium and fetus ⁇ were cut in a Petri dish, and the fetuses separated from each placenta were removed one by one, and the fetuses were collected in another Petri dish containing a new HBSS solution.
  • the upper part of the fetus was cut off from the chest, and the jaw was penetrated from the abdomen with a syringe needle, and then fixed on a wax table with the chin.
  • Cell culture medium Minimum essential 'medium (Minimum Essentia 1 Medium, Gibco) with fetal bovine serum (F1ow) Add 10%, and add 100 units (1111 ⁇ 1: 5) / 1 and 100 1 m of Penicillin G Potassium (Meiji Seika) and Streptomycin (Banyu Pharmaceutical Co., Ltd.), respectively. ) And fluorodeoxyperidine
  • culture medium (A) (Fluo rodeoxyuridene, Sigma) were added to give a concentration of 20 M each (hereinafter referred to as “culture medium (A)”).
  • SCG neurons For SCG neurons: Excess connective tissue around each SCG was removed with sterile forceps under a stereomicroscope (Nikon), and fresh HBSS solution was used in a Petri dish. After washing three times, SCGs were added to lml of HBSS solution containing collagenase (Wako) power (mg / ml) and incubated at 37 C for 30 minutes. During this time, the solution was stirred 2-3 times. Thereafter, SCG neurons were dissociated by injecting and removing SCGs 70 to 80 times using a pasteur pit whose tip area was further narrowed by a burner. The cell concentration of this SCG nerve cell suspension was determined by the cell count method using Tripan blue staining.
  • culture solution (C) A solution obtained by dissolving the chromone derivative of the present invention in the added solution (hereinafter referred to as “culture solution (C)”, antibody concentration: 4.17 uI / ml) was added to a well, and the culture was continued for another 2 days.
  • the chromone derivative was weighed and dissolved so that the concentration in the culture solution (C) became 50 gZm1. After culturing with a culture solution (C) containing no chromone derivative, Group. After completion of the 2-day culture test, the number of surviving cells and the number of dead cells in each cell were counted under a microscope by the cell count method using trypan blue staining, and the ratio of the number of dead cells was calculated.
  • the chromone derivative of the present invention had a remarkable nerve cell death inhibitory effect. Therefore, the chromone derivative of the present invention was confirmed to be useful as a nerve cell death inhibitor that can be used for the treatment of Alzheimer's disease, Down's syndrome, vascular dementia, Parkinson's disease, amyotrophic lateral sclerosis, and the like. Was done.
  • Mstar male rats (Nippon Charles River Inc., 8 weeks old) were used after about 18 hours of fasting. The animals were preliminarily reared for at least one week at a temperature of 23 ⁇ 2 t and a humidity of 55 ⁇ 10% and used for the experiment. Rats were allowed to freely ingest solid feed (MF, Oriental Yeast Kogyo Co., Ltd.). The number of animals subjected to the test was 3 per group.
  • chromone derivatives were suspended in Tween 80 physiological saline and administered orally by gavage at a dose of 100 mg / kg / 10 ml using a metal probe.
  • a rat was filled with a heparin physiological saline solution (200 U / tnl) into a femoral artery under ether anesthesia, and fixed to a ballman cage. After awakening from anesthesia, the chromone derivative of the present invention is administered, and blood is collected from the force neura at approximately 350 ui every 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after administration.
  • a heparin physiological saline solution 200 U / tnl
  • Rat plasma 501 was shaken for 20 minutes after adding 150 “1 of an internal standard substance (100 ⁇ g / ml butyl P-hydroxybenzoate in methanol) and 50 ⁇ l of methanol for HPLC. Then, the mixture was shaken for 20 minutes at 3000 rpm and 4 ° C. Centrifuge for 20 minutes, transfer the supernatant to another tube, evaporate to dryness in a freeze centrifuge, and re-dissolve in 1% methanol phosphate (3 min, shake for 3 min, sonicate) Then, 40 1 was injected into the HPLC.
  • an internal standard substance 100 ⁇ g / ml butyl P-hydroxybenzoate in methanol
  • HPLC methanol phosphate
  • UV detector SPD-10A (Shimadzu Corporation)
  • the maximum plasma concentration (Cmax) and the time to reach the maximum plasma concentration (Tmax) were determined from the measured values.
  • the time to the final measurement point-area under the plasma concentration curve (JC0-lim) and time to infinity-area under the blood concentration curve (JCO-ini) were calculated by the trapezoidal method.
  • Nerve conduction tests (Latest Medicine, 50, 771-780, 1995), which is said to be the most useful means for diagnosing peripheral neuropathy complicated by diabetes patients, were performed on the chromone derivative of the present invention. .
  • the chromone derivative of the present invention was suspended in 1% Tween 80 at a concentration of 1 mgZkg, and orally administered for 4 weeks from 2 weeks after STZ administration. Those to which 1% Tween 80 containing no chromone derivative of the present invention was similarly administered were used as diabetes controls.
  • MNCV of rat tail nerve was measured according to Niyoshi and Goto (Electroncephalogaphy and Clinical Neurophysiology, 35, 125-131, 1973). After anesthesia by intraperitoneal administration of Nembutal 50 mg Zkg, the tail nerve was the subject nerve, the site 1 cm distal from the K portal was the first stimulation point, the site 5 cm distal was the second stimulation point, and the peripheral nerve was 3 cm further. MNCV was measured with a recording point. MNCV was determined by the following equation.
  • the tail was kept in a paraffin thermostat at 37 ° C, and a temperature sensor (thermosensitive injection needle THR-NST, Shibaura Electronics) was placed 3 to 4 cm from the anus, and an Animal Branket Controller (ATB-1100) was installed. , Nihon Kohden) with tail temperature of 37. C was confirmed.
  • a temperature sensor thermosensitive injection needle THR-NST, Shibaura Electronics
  • ATB-1100 Animal Branket Controller
  • the chromone derivative of the present invention has been confirmed to have the ability to inhibit phosphodiesterase activity via the sciatic god, and has been shown to be effective for peripheral neuropathy associated with diabetic patients> 'Shown.
  • 1 to 1 were uniformly mixed, and were compression-molded with a tableting machine to obtain 200 tablets per tablet.
  • Example 7 4 One tablet contains 20 mg of the compound obtained in Example 8, and 10 to 25 tablets daily for an adult are divided into several doses.
  • Example 7 4 One tablet contains 20 mg of the compound obtained in Example 8, and 10 to 25 tablets daily for an adult are divided into several doses.
  • part of 1, 4 and 2 are mixed uniformly, compression molded, then ground, mixed with the remaining amount of 3 and 2, and compressed and molded with a tableting machine to make one tablet 200 mg tablets were obtained.
  • One tablet contains 20 mg of the compound obtained in Example 45, and an adult is to take 10 to 25 tablets a day in several doses.
  • 1, 2 and 2 are uniformly mixed, screwed together by a conventional method, granulated by an extruder, dried and crushed, and then mixed with 3 and ⁇ to form a tableting machine. Then, compression molding was performed to obtain a tablet of 200 mg per tablet.
  • One tablet contains 20 mg of the compound obtained in Example 37, and an adult takes 10 to 25 tablets a day in several doses.
  • 1 g of this granule contains 100 mg of the compound obtained in Example 12, and 2 to 5 g of an adult 1 is taken in several doses.
  • 1 g of this granule contains 100 mg of the compound obtained in Example 57 (4), and 2 to 5 g of an adult is taken several times a day.
  • One capsule of this capsule contains 20 mg of the compound obtained in Example 34, and the adult is to take 10 to 25 capsules a day in several doses.
  • the chromone derivative of the present invention has a nerve cell death inhibitory effect and is useful as a therapeutic drug for diseases caused by nerve cell death.

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  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des dérivés de chromone représentés par la formule générale (I) ou leurs sels pharmaceutiquement acceptables, ainsi que des inhibiteurs de la mort des cellules nerveuses, contenant lesdits dérivés sous forme de principe actif. Dans la formule, R représente carboxyalkyle, carboxyalcényle, alcoxyalkyle, alcoxycarbonyle, alkylthioalkyle, alkylsulfinylalkyle, alkylsulfonylalkyle, alkylsulfonyle, alkylcarbonyloxyalkyle, alcoxycarbonylalkyle, alcoxycarbonylalcényle, alkyle ramifié, acyle aliphatique, alcoxycarbonyle, carbamoyle éventuellement substitué, thiocarbamoyl éventuellement substitué, 1-pipéridinylcarbonyle éventuellement substitué, 1-pyrrolidinylcarbonyle éventuellement substitué, 1-pipérazinylcarbonyle éventuellement substitué, morpholinocarbonyle éventuellement substitué, benzène-sulfonyle éventuellement substitué, alcényle, 2-acétoxy-2-méthylpropionyle, benzoyle, alcoxybenzoyle, nitrobenzoyle, acétoxybenzoyle, aminobenzoyle, morpholinométhylbenzoyle, thiophène-carbonyle, furoyle, pyridine-carbonyle, phénoxycarbonyle ou diphénoxyphosphoryle.
PCT/JP1997/002402 1996-09-11 1997-07-10 Derives de chromone et inhibiteurs de la mort des cellules nerveuses contenant lesdits derives Ceased WO1998011086A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/240830 1996-09-11
JP8240830A JP2000016988A (ja) 1996-09-11 1996-09-11 クロモン誘導体

Publications (1)

Publication Number Publication Date
WO1998011086A1 true WO1998011086A1 (fr) 1998-03-19

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Application Number Title Priority Date Filing Date
PCT/JP1997/002402 Ceased WO1998011086A1 (fr) 1996-09-11 1997-07-10 Derives de chromone et inhibiteurs de la mort des cellules nerveuses contenant lesdits derives

Country Status (2)

Country Link
JP (1) JP2000016988A (fr)
WO (1) WO1998011086A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7786057B2 (en) * 2007-02-08 2010-08-31 Infineum International Limited Soot dispersants and lubricating oil compositions containing same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01228914A (ja) * 1988-03-09 1989-09-12 Tsumura & Co アルドースリダクターゼ阻害剤
WO1992009594A1 (fr) * 1990-11-30 1992-06-11 Tsumura & Co. Derive de benzopyrone et inhibiteur de reductase d'aldose contenant ce derive en tant qu'ingredient actif

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01228914A (ja) * 1988-03-09 1989-09-12 Tsumura & Co アルドースリダクターゼ阻害剤
WO1992009594A1 (fr) * 1990-11-30 1992-06-11 Tsumura & Co. Derive de benzopyrone et inhibiteur de reductase d'aldose contenant ce derive en tant qu'ingredient actif

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7786057B2 (en) * 2007-02-08 2010-08-31 Infineum International Limited Soot dispersants and lubricating oil compositions containing same

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